This invention was made with government support under Grant No. 91HL07 awarded by the National Heart Lung and Blood Institute, giving the federal government certain rights in the invention. In addition, the invention described herein was made in the performance of work under a NASA contract and is subject to the provisions of Section 305 of the National Aeronautics and Space Act of 1958, Public Law 85-568 (72 Stat. 435; 42 U.S.C. 2457).
A. Field of the Invention
This invention relates to the medical diagnosis and treatment of arterial disease by means of temperature differential sensing, and particularly, infrared-sensing with devices such as temperature probes, cameras, and catheters. In particular, the invention provides catheters and methods of using catheters to diagnose arterial diseases detectable by thermal discrepancies in the arterial wall.
B. Description of the Related Art
Plaque Physiology
Atherosclerotic coronary artery disease is the leading cause of death in industrialized countries. An atherosclerotic plaque is a thickened area in the wall of an artery. Typically, patients who have died of coronary disease may exhibit as many as several dozen atherosclerotic plaques; however, in most instances of myocardial infarction, cardiac arrest, or stroke, it is found that only one of these potential obstructions has, in fact, ruptured, fissured, or ulcerated. The rupture, fissure, or ulcer causes a large thrombus (blood clot) to form on the inside of the artery, which may completely occlude the flow of blood through the artery, thereby injuring the heart or brain. A major prognostic and diagnostic dilemma for the cardiologist is how to predict which placque is about to rupture.
Most ruptured plaques are characterized by a large pool of cholesterol or necrotic debris and a thin fibrous cap with a dense infiltration of macrophages. The release of matrix-digesting enzymes by the cells is thought to contribute to plaque rupture. Other thromboses are found on non-ruptured but inflamed plaque surfaces.
Inflammation in an arterial plaque is the result of a series of biochemical and mechanical changes in the arterial wall. Plaque, a thickening in the arterial vessel wall results from the accumulation of cholesterol, proliferation of smooth muscle cells, secretion of a collagenous extracellular matrix by the cells, and accumulation of macrophages and, eventually, hemorrhage (bleeding), thrombosis (clotting) and calcification. The consensus theory is that atherosclerotic plaque develops as a result of irritation or biochemical damage of the endothelial cells.
The endothelial cells which line the interior of the vessel prevent inappropriate formation of blood clots and inhibit contraction and proliferation of the underlying smooth muscle cells. Most investigators believe that atherosclerotic plaques can develop when endothelial cells are damaged or dysfunctional. Dysfunction in endothelial cells is typically produced as a result of injury by cigarette smoke, high serum cholesterol (especially oxidized low density lipoprotein), hemodynamic alterations (such as those found at vessel branch points), some viruses (herpes simplex, cytomegalovirus) or bacteria (e.g., Chlamydia), hypertension, some hormonal factors in the plasma (including angiotensisn II, norepinephrine), and other factors as yet unknown. As a result of these gradual injuries to the endothelial cells, an atherosclerotic plaque may grow slowly over many years. However, it is now well documented that if a plaque ruptures, it often grows abruptly.
When plaque rupture develops, there is hemorrhage into the plaque through the fissure where the surface of the plaque meets the bloodstream. Blood coagulates (forms a thrombus) quickly upon contact with the collagen and lipid of the plaque. This blood clot may then grow to completely occlude the vessel or it may remain only partially occlusive. In the latter case, the new clot quite commonly becomes incorporated into the wall of the plaque, creating a larger plaque.
Plaques at Risk of Rupturing
Considerable evidence indicates that plaque rupture triggers 60% to 70% of fatal myocardial infarctions and that monocyte-macrophages contribute to rupture by releasing metalloproteinases (e.g., collagenases, stromelysin) which can degrade and thereby weaken the overly fibrous cap. Van der Wal, et al., Circulation 89:36-44 (1994); Nikkari, et al., Circulation 92:1393-1398 (1995); Falk, et al., Circulation 92:2033-20335 (1995); Shah, et al., Circulation 244 (1995); Davies, et al., Br Heart J 53:363-373 (1985); Constantinides, J Atheroscler Res 6:1-17 (1966). In another 25% to 30% of fatal infarctions, the plaque does not rupture, but beneath the thrombus the endothelium is replaced by monocytes and inflammatory cells. Van der Wal, et al., Circulation 89:36-44 (1994); Farb, et al., Circulation 92:1701-1709 (1995). These cells may both respond to and aggravate intimal injury, promoting thrombosis and vasoconstriction. Baju, et al., Circulation 89:503-505 (1994).
Unfortunately, neither plaque rupture nor plaque erosion is predicable by clinical means. Soluble markers (P-selectin, von Willebrand factor, angiotensen-converting enzyme, C-reactive protein, D-dimer; Ikeda, et al., Circulation 92:1693-1696 (1995); Merlini, et al., Circulation 90:61-8 (1994); Berk, et al., Am J Cardiol 65:168-172 (1990)) and activated circulating inflammatory cells are found in patients with unstable angina pectoris, but it is not yet known whether these substances predict infarction or death. Mazzone, et al., Circulation 88:358-363 (1993). It is known, however, that the presence of such substances cannot be used to locate the involved lesion.
Low-shear regions opposite flow dividers are more likely to develop atherosclerosis, (Ku, et al., Arteriosclerosis 5:292-302 (1985)), but most patients who develop acute myocardial infarction or sudden cardiac death have not had prior symptoms, much less an angiogram. Farb, et al., Circulation 92:1701-1709 (1995).
Certain angiographic data has revealed that an irregular plaque profile is a fairly specific, though insensitive, indicator of thrombosis. Kaski, et al., Circulation 92:2058-2065 (1995). These stenoses are likely to progress to complete occlusion, while less severe stenoses are equally likely to progress, but less often to the point of complete occlusion. Aldeman, et al., J Am Coll Cardiol 22:1141-1154 (1993). However, because hemodynamically nonsignificant stenoses more numerous than critical stenoses and have not triggered collateral development, those which do abruptly occlude actually account for most myocardial infarctions. Ambrose, et al., J Am Coll Cardiol 12:56-62 (1988); Little, et al., Circulation 78:1157-1166 (1988).
Moreover, in postmortem studies, most occlusive thrombi are found over a ruptured or ulcerated plaque that is estimated to have produced a stenosis of less than 50% in diameter. Shah, et al., Circulation 244 (1995). Such stenoses are not likely to cause angina or a positive treadmill test. (In fact, most patients who die of myocardial infarction do not have three-vessel disease or severe left ventricular dysfunction.) Farb, et al., Circulation 92:1701-1709 (1995).
In the vast majority of plaques causing a stenosis less than or equal to 50%, the surface outline is uniform, but the deep structure is highly variable and does not correlate directly with either the size of the plaque or the severity of the stenosis. Pasterkamp, et al., Circulation 91:1444-1449 (1995); Mann and Davies Circulation 94:928-931 (1996).
Certain studies have been conducted to determine the ability to identify plaques likely to rupture using intracoronary ultrasound. It is known that (1) angiography underestimates the extent of coronary atherosclerosis, (2) high echo-density usually indicates dense fibrous tissue, (3) low echo-density is a feature of hemorrhage, thrombosis, or cholesterol, and (4) shadowing indicates calcification. Yock, et al., Cardio 11-14 (1994); McPerhson, et al., N Engl J Med 316:304-309 (1987). However, recent studies indicate that intra-vascular ultrasound technology currently cannot discriminate between table and unstable plaque. De Feyter, et al., Circulation 92:1408-1413 (1995).
The rupture process is not completely understood, but it is known that the plaques most likely to rupture are those that have both a thin collagen cap (fibrous scar) and a point of physical weakness in the underlying plaque. It is known that plaques with inflamed surfaces or a high density of activated macrophages and a thin overlying cap are at risk of thrombosis. Van der Wal, et al., Circulation 89:3644 (1994) Shah, et al. , Circulation 244 (1995); Davies, et al., Br Heart J 53:363-373 (1985); Farb, et al., Circulation 92:1701-1709 (1995); Van Damme, et al., Cardiovasc Pathol 3:9-17 (1994). Such points are thought to be located (as determined by modeling studies and pathologic analysis) atjunctures where pools of cholesterol meet a more cellular and fibrous part of the plaque. Typically, macrophages (inflammatory cells), which produce heat, have been found at these junctures. Since these inflammatory cells release enzymes capable of degrading the collagen and other components of the extracellular matrix, it is thought that they are crucial to the process of plaque rupture or fissuring.
Transplant Vasculopathy
Inflammation also plays an important role in the rejection of transplanted organs, a process which begins by an attack of host T lymphocytes in the grafted donor organ""s endothelial cells. Yeung et al. J. Heart Lung Transplant. 14:S215-220 (1995); Pucci et al. J. Heart Transplant. 9:339-45 (1990); Crisp et al. J. Heart Lung Transplant. 13:1381-1392 (1994). Recruitment and proliferation of inflammatory and smooth muscle cells are heat-generating processes, whose effects are detectable in advance of the detection of vessel narrowing using stress tests, ultrasound, or angiography. Johnson et al. J. Am. Coll. Cardiol. 17: 449-57 (191); St. Goar et al. Circulation 85:979-987 (1992). In addition to the host attack of xe2x80x9cnon-selfxe2x80x9d antigens of the donor organs, many transplanted tissues develop cytomegalovirus infections, an event that is also heat-generating. Grattan et al. JAMA 261:3561-3566 (1989). These events in transplant physiology are ones for which it would be valuable to track in patients recovering from such surgery.
Restenosis
Another serious problem in diagnostic cardiology is restenosis, a renarrowing of an artery that has undergone one or more interventional techniques to relieve an original stenosis (caused by plaque). Such techniques include balloon angioplasty, atherectomy (shaving or cutting the plaque), and laser angioplasty. Balloon angioplasty of the coronary arteries is a major advance in treatment and has been performed on hemodynamically significant coronary stenoses (those that are 70% to 99% of the cross-sectional diameter of the vessel) with a success rate of 90%. In about 40% of the patients, however, restenosis occurs in the vessel and most of the benefit gained by the procedure is lost. Thus, another major diagnostic and prognostic dilemma for cardiologists not readily addressed by prior art devices or methods is predicting which patients will develop restenosis.
Restenosis may occur when the removal of plaque by angioplasty or atherectomy injures the artery wall. The injury to the vessel wall causes the smooth muscle cells at that site to proliferate and to secrete an extracellular matrix which again narrows the artery. Both cell proliferation and secretion are exergonic (heat-generating) processes. Additionally, it is known that macrophage concentration in a vessel is correlated to the risk of restenosis.
Many factors have been reported to predict which patients will develop restenosis. However, these studies are markedly at odds with each other and no factor has been strongly predictive of the restenosis process. Thus, cigarette smoking, hypertension, hypercholesterolemia, unstable angina, age, sex, and many other factors have been only weakly predictive, at best.
A number of approaches and devices have been proposed to diagnose or treat vascular obstructions. U.S. Pat. No. 3,866,599 relates to a fiberoptic catheter for insertion into the cardiovascular system for the measurement of oxygen in blood. For the purpose of detecting oxygenation levels in the blood, optical fibers are used to first project infra-red and red light at the catheter tip into the blood. The infra-red and red light reflected by the blood is then returned through the optical fibers to a an oximeter. The ratio of infra-red light reflected to that absorbed by the blood is proportional to the oxygen saturation in the blood. This catheter design is also one wherein there is at the distal end of the element a recess preventing the ends of the fibers from contacting the vessel wall and an exterior sleeve which can be expanded to further space the fibers from the wall of the vessel. However, the fiberoptic catheter of this patent does not permit detection of heat.
In some prior art devices, temperature sensing elements have been used. U.S. Pat. No. 4,752,141 relates to fiberoptic sensing of temperature and/or other physical parameters using a system comprising (1) an optical fiber (2) means including a source of visible or near visible electromagnetic radiation pulses at one end of the fiber for directing the radiation along the fiber to another end of the fiber (3) a sensor positioned at or near the end of the fiber in a manner to receive the radiation, modulate it by the temperature, and redirect the modulated radiation back through the optical fiber to the sensor (4) the sensor comprising at least one optical element in the path of the source of radiation whose optical properties vary in response to the magnitude of temperature changes and (5) means positioned at the end of the fiber receiving the modulated radiation for measuring a function related to the time of the resulting luminescent radiation intensity decay after an excitation pulse indicating the temperature of the sensor. These temperature sensors were designed to physically contact a surface and were built with an elastomeric substance at the end of the fiber to which a thin layer of phosphor material had been deposited. The phosphor reacts to the temperature and emits radiation which travels up the fiber and is detected by the sensor. Contact temperature determinations require the ability of the catheter to be placed in contact with the locus whose temperature is to be measured.
U.S. Pat. No. 4,986,671 relates to a fiber optic probe with a single sensor formed by a elastomeric lens coated with a light reflective and temperature dependent material over which is coated a layer of material that is absorptive of infrared radiation thereby allowing a determination of characteristics of heat or heat transfer. One application is in a catheter for providing pressure, flow and temperature of the blood in a blood vessel.
Other methods utilizing differing means for heat detection are known. The sensitivity and/or toxicity of these devices is unknown. U.S. Pat. No. 4,140,393 relates to the use of birefringement material as a temperature probe. U.S. Pat. No. 4,136,566 suggests the use of the temperature dependent light absorption characteristics of gallium arsenide for a temperature sensor. U.S. Pat. No. 4,179,927 relates to a gaseous material having a temperature dependent light absorption.
Other approaches utilize excitation techniques to detect heat. U.S. Pat. No. 4,075,493 relates to the use of a luminescent material as a temperature sensor, exciting radiation of one wavelength range being passed along the optical fiber from the measuring instrument, and temperature dependent luminescent radiation being emitted from the sensor back along the communicating optical fiber for detection and measurement by the instrument. It is the luminescent sensor technology which has found the greatest commercial applicability in fiber optic measurements, primarily for reasons of stability, wide temperature range, ability to minimize the effect of non-temperature light variations, small sensor size and the like.
An example of a luminescent fiberoptic probe that can be used to measure the velocity of fluid flow, among other related parameters, is given in U.S. Pat. No. 4,621,929. Infrared radiation is directed to the sensor along the optical fiber and is absorbed by a layer of material provided for that purpose. Once heated, the sensor is then allowed to be cooled by a flow of fluid, such cooling being measured by the luminescent sensor. The rate of cooling is proportional to the heat transfer characteristics and flow of the surrounding liquid.
U.S. Pat. No. 4,995,398 relates to the use of thermography during the course of bypass heart surgery for the purpose of checking the success of the operation before closing the chest cavity. This patent describes the use of a scanning thermal camera, image processing, temperature differentials and displaying images in real time. The invention relies on the use of a cold injectate which when it mixes with warmer blood provides images captured on a thermal camera focusing on the heart to detect stenoses at the sites of distal anastomoses.
U.S. Pat. No. 5,046,501 relates to a method of identifying atherosclerotic plaque versus structurally viable tissues using a fluorescent beam at a single excitation wavelength of between 350 and 390 nm preferably from a laser which allows differentiation of these tissues. No catheter was used in the examples of the patent. Thus, in situ imaging is not disclosed or taught by this patent. Moreover, no technique is described by this patent for predicting plaque rupture, restenosis or transplant vasculopathy.
U.S. Pat. No. 5,057,105 relates to a hot tip catheter assembly comprising a heater, a cap, a thermocouple, power leads, and a central distal lumen to position the catheter in the artery. The thermocouple is included to continuously monitor the heating of the catheter tip in order to prevent overheating. The tip when properly placed on a plaque build up, melts the plaque.
U.S. Pat. No. 5,109,859 relates to ultrasound guided laser angioplasty comprising a laser at the tip of a catheter, an ultrasound device also at the tip of the laser for guidance, and a proximal occlusion balloon to provide stabilization and a blood free environment. This patent apparently also relates to estimating the mass of a plaque tissue. There is no teaching that the ultrasound device of the patent can distinguish histologicai features (i.e., what cells and extracellular matrix are within the plaque). Thus, it is not likely that such a device could be used to predict plaque rupture. Indeed, recent studies have found that intravascular ultrasound cannot identify which plaques are at risk of rupturing. de Feytia Circulation 92:1408-13 (199).
U.S. Pat. No. 5,217,456 relates to an intra-vascular guidewire-compatible catheter which has a source of illumination and a synchronous fluorescence detector. Light in a wavelength that induces fluorescence in tissues emanates radially from an aperture on the side of the catheter. Fluorescence emitted from the tissues enters the catheter through the same aperture and is conveyed to a spectral analyzer. This information can be used to differentiate healthy tissue from atherosclerotic plaque. However, this device does not distinguish between plaque on the basis of heat differential.
U.S. Pat. No. 5,275,594 relates to methods and apparatus for distinguishing between atherosclerotic plaque and normal tissue by analyzing photoemissions from a target site. The system includes a source of laser energy for stimulation of fluorescence by non-calcified versus calcified atherosclerotic plaque, and an analyzing means for determining whether a spectrum of fluorescence emitted by a tissue represents calcified or non-calcified atherosclerotic plaque at a target site, based upon the time domain signal of calcium photoemission following fluorescent excitation of the calcium. When atherosclerotic plaque is identified, laser energy is used to ablate the plaque.
Prior art approaches to intravascular arterial diagnosis and repair have been numerous yet have failed to provide certain capabilities. In particular, such prior art catheters and methods have failed to provide means for detecting and treating atherosclerotic plaque since they have not been able to differentiate between those plaques at risk of rupturing and occluding and those that are not presently at such risk even if they are capable of determining the presence or absence of calcification of the plaque. Similarly, prior art approaches have not provided effective means for identifying specific arterial sites at risk for arterial restenosis after angioplasty or atherectomy. Prior art approaches have also failed to provide practical and effective means for detecting transplant vasculopathy. Neither have prior art approaches been able to effectively identify patients who have arterial wall areas of lower rather than higher temperature, such as areas of extensive scarring, lipid pools where there is no cellular infiltration, or areas of hemorrhage and thrombosis which have yet to be colonized by inflammatory cells.
The present invention overcomes at least some of the failures of the prior art by providing an infrared-sensing catheter for detecting heat-producing inflammatory cells and vessel wall cells, and thus predicting the behavior of injured blood vessels in medical patients. The catheters and methods of the present invention provide effective means for detecting and treating atherosclerotic plaque which is capable of differentiating between, among other pathologies, those plaques at risk of rupturing and occluding and those that are not presently at risk. The catheters and methods of the present invention also provide effective means for identifying specific arterial sites at risk for arterial restenosis after angioplasty or atherectomy, or which patients are at risk due to vasculopathy, or tissue rejection. The catheters and methods of the present invention also are capable of effectively identifying patients who have arterial wall areas of unusually low temperature and which represent previously undetected arterial at-risk areasxe2x80x94just as excess heat can identify regions at risk due to inflammation, sub-normal heat (areas cooler than the rest of a vessel) indicates a lack of actively metabolizing healthy cells (since heat in the body results from actively metabolizing cells). Non-cellular areas are typically regions of hemorrhage, thrombosis, cholesterol pools, or calciumxe2x80x94all indicators of high risk plaques. The invention""s devices and methods achieve these ends by identifying and analyzing thermal discrepancies in the wall temperature of blood vessels.
The invention in one regard relates to apparatus for analyzing optical radiation of a vessel. In another regard, the invention relates to methods for analyzing optical radiation, which methods are best preferably achieved using the apparatus of the invention.
Optical radiation of particular interest in the invention is that radiation which falls in the optical spectrum in the wavelength interval from about 2-14 xcexcm. An attractive feature of infrared is its penetration through calcium (relative to white light and ultrasound). Benaron, et al., J Clin Monit 11:109-117 (1995).
The vessels of particular interest in the invention are those vessels where the access to a surface of which is problematic. Thus, where the internal diameter of a vessel is too small for ready access by a traditional temperature probe (i.e., a contact thermometer or thermocouple), the apparatus and methods of the invention will find utility. Similarly where the vessel, while of sufficiently large internal diameter for access by a temperature probe, has one or others of its openings narrowed, occluded or otherwise blocked, the apparatus and methods of the invention will find utility. Thus, of particular interest in application of the apparatus and methods of the invention are vessels of the body, including vessels circulating and transporting sera (i.e. blood) such as arteries, veins, sinuses, heart cavities and chambers.
The invention relates to apparatus and methods in which there is at least one optical fiber used which is capable of transmitting optical radiation from a distal end of the fiber, usually inside a vessel, to a proximal end of the fiber, usually outside the vessel. Optical fibers of the invention will exhibit certain key parameters related to their ability to transmit wavelengths in the region of 2-14 xcexcm. These key parameters include optical transparency, flexibility and strength. The optical fibers of the invention are those which may be extruded in ultrathin diameters and which transmit over the appropriate infra-red spectral region. The infrared fiberoptic can be constructed from a variety of substances known to those of skill in the art such as zirconium fluoride (ZrF4), silica, or chalcogenide (AsSeTe). ZrF4 fibers are well suited to the apparatus and methods of the invention because such fibers have  greater than 90% transmission capabilities over 1 meter for small diameters.
The optical fibers useful in the apparatus and methods of the invention will also be ones capable of placement proximate to a locus of a wall of the vessel being investigated. This criterion is achieved in part by the flexibility of the fiber optic. In additional part, this criterion is met by the ultrathin nature of the diameter of the fiber optic.
The apparatus and methods of the invention also utilize a balloon which encases a distal end of the fiber. The balloon, in one embodiment, may be one which is transparent to the optical radiation of interest. In that instance, optical radiation originating outside the balloon is transmitted through the outer surface of the balloon to the inner surface of the balloon and on to the entry point for optical radiation into the optical fiber. It is important, in this embodiment, for there to be little if any absorption, reflection or other diversion of the optical radiation emanating from the source (i.e., the vessel wall, a locus such as a plaque locus) during its transmission through the surfaces of the balloon. Such unwanted absorption may be caused by blood or other body fluids. Therefore, transparency for purposes of the invention means an ability to transmit substantially all optical radiation from a particular source through the balloon surfaces to the optical fiber.
It is important, in this embodiment, for there to be substantially total conduction of the heat, while having substantially no loss of the heat emanating from the source (i.e., the vessel wall, a locus such as a plaque locus) as it contacts the outer surface of the balloon. Therefore, opacity (opaque) for purposes of the invention means an ability to absorb substantially all optical radiation from a particular source on the outer balloon surface. Thereafter, the inner surface of the balloon will re-emit a proportional amount of radiation to that absorbed on the outer surface immediately adjacent the locus originating the radiation. This re-emitted radiation will be detectable by the fiber optic system encased inside the balloon.
The apparatus and methods of the invention also utilize a detector capable of detecting a difference in the optical radiation of interest, between the locus and the average optical radiation along the vessel wall being investigated. In certain preferred embodiments, the detector of the invention is one which has a sensitivity capable of detection of differences in infra-red radiation as small as 50xc2x0 mK, and in the range of 10 to 100xc2x0 mK.
Where the balloon is one which is transparent to the radiation directly emitted from the locus or from the vessel wall portions outside the specific locus, the detector will be one capable of detecting the radiation which is transmitted through the balloon""s outer and inner surfaces. Where the balloon is one which is opaque to the radiation directly emitted from the locus or from the vessel wall portions outside the specific locus, the detector will be one capable of detecting the radiation which is re-emitted from the balloon""s inner surface opposite the balloon""s outer surface which is directly in contact with the locus.
In preferred embodiments the apparatus and methods of the invention will rely on detection of optical radiation in the infra-red radiation ranges. In particular, as noted above, ranges of 2-14 micrometers are of particular interest in the apparatus and methods of the invention. Referring to FIG. 2, it can be seen that it is possible to plot curves for radiation (numbers of photonsxc3x971xc3x971017) being emitted by black bodies held at differing constant temperatures (T1, T2 and T3 each refer to temperatures in the range of 300-310xc2x0 K which vary from one another increasingly by 1xc2x0 K) in the wavelength range of 3 up to 6 micrometers. It can also be seen in the inset to FIG. 2, that in the range of approximately 5.3 to 5.6 micrometers, black bodies held at constant temperatures in the range of 300-310xc2x0 K and differing from one another by only a single degree, appear as easily distinguishable curve segments, emitting photons from these black bodies in the range of approximately 0.21xc3x971017 to 0.40xc3x971017 photons. Thus, it is preferred to select a wavelength for sampling the radiation from the wall and specific locus on the wall of a vessel which will provide similarly distinguishable curves.
In certain preferred embodiments, the apparatus and methods of the invention may comprise at least two fibers, although the use of greater than two fibers is clearly possible where merited, such as when detection along the axis of the vessel is preferred at greater than a single position simultaneously. In other preferred embodiments, where at least two fibers are utilized, at least one of the fibers is a reference fiber and another of the fibers is a signal fiber. The signal fiber is a fiber designed to transmit all optical radiation focused into its length from its distal end to its proximal end. Conversely, the reference fiber is a fiber which is used as a control against which the signal fiber transmissions may be compared. Thus, where optical radiation exiting the proximal end of the signal fiber is compared to that exiting the proximal end of the reference fiber, a determination can be readily made as to relative amounts of optical radiation exiting the signal fiber which is due to other than optical radiation emitted by the locus of interest.
The apparatus of the invention may also be optically connected at the distal end of the signal fiber to an optically reflective surface capable of directing optical radiation arising radially to said distal end, and on into said fiber. U.S. patent application Ser No. 08/434,477 in which certain of the present inventors are named co-inventors, and which is incorporated herein by reference, describes such an optically reflective surface. As opposed to the signal fiber, the reference fiber will typically be coated on its distal end with a material that substantially prevents optical radiation from entering it.
The apparatus of the invention is also one in which the inner surface of the opaque occluding balloon emits a black body spectrum modulated by the transmission spectrum of the balloon. The balloon, upon inflation, will substantially limit flow of fluids within the vessel. The flow limitation required is one in which only so much flow occurs as will not cause a rise or fall in average background IR radiation along the vessel wall immediately distal the inflated balloon. In addition, in preferred embodiments, the apparatus of the invention is one where the balloon, upon inflation, substantially excludes the presence of intervesicular fluids between the fibers inside the balloon and the wall of the vessel most proximate to the test locus.
In use, the apparatus of the invention will be placed along an axis of the vessel. in this manner, it will be possible to bring the diagnostic fiber array into close proximity with a locus to be diagnosed. In certain preferred embodiments, the locus will be one which contains plaque. In particular, the apparatus as previously noted will be useful in detecting among those plaques with which it is brought into proximity, whether a given plaque is one at risk of rupturing. In most instances, the apparatus of the invention will be used to diagnose thermal discrepancies on the interior wall of a vessel.
The apparatus of the invention is in its most preferred embodiments a catheter. Typical of catheters used inside of blood vessels, the catheter of the invention will be one designed for use with a guidewire. The guidewire will allow optional removal and reinsertion at the discretion of the surgeon, for example where after diagnosing a plaque at risk of rupturing using the catheter of the invention, the surgeon may wish to bring another diagnostic device or a therapeutic device such as a laser into the same position next to the problematic plaque.
The apparatus of the invention is also one where the detector is preferably optically connected to a proximal end of the fiber, and if there is more than one fiber, to a proximal end of each of the fibers. In preferred embodiments, the detector will be a multi-wavelength radiometer.
Such a radiometer will preferably be a spinning circular variable filter whose transmission wavelength is a function of its angle of rotation. In such a filter, it is possible to prevent transmission of all but a narrow band of wavelengths of light by adjusting the rotational angle. Said differently, such a filter can be made to be transparent to highly selected wavelengths by its rotational characteristics. Thus, in certain embodiments, the filter will be one transparent to radiation with a wavelength of approximately between 2 to 6 micrometers. In highly preferred embodiments, the filter will be transparent to radiation with a wavelength of approximately 3 micrometers.
One of the keys to this invention as it relates to the apparatus, is that it automatically provides a reference for each spectrum by sampling approximately 3 xcexcm. For the range of temperatures expected in biological organisms. 300-310xc2x0 K, the blackbody spectrum at this wavelength is essentially the same. This provides a zero for each signal and locks down the low wavelength side of the signal. Without this, there would be no way to fit a signal to a blackbody spectrum since the vertical scale would be xe2x80x9cunfixedxe2x80x9d.
Where the apparatus of the invention utilizes the transmitted information from more than one fiber through a filter for comparative purposes, it will be preferred to utilize an offset in the distal fiber ends. Thus, where the distal ends of the signal fiber and the reference fiber are offset from one another, the offset will be at a distance sufficient to allow sampling of radiation emitted from either fiber to pass the filter at a substantially identical location on the filter.
The apparatus of the invention when used in conjunction with a radiometer, will preferably be one optically connected to at least one photoelectric device capable of converting the transmitted radiation into an electrical signal. The photoelectric device is preferably one electrically connected to a device capable of digitizing the electrical signal (a digitizer).
Once the apparatus of the invention has created a digitized signal, the digitized signal is mathematically fitted to a curve selected from a spectrum of curves for black bodies held at temperatures between approximately 300-310xc2x0 K. The curves of the controlled black bodies are those plotted as numbers of photons emitted from each black body for each wavelengths. In instances where such a digitized signal is to be used to diagnose thermal discrepancies in the interior wall of a blood vessel, the particular selection of black body control curves will be made with the knowledge of typical temperatures of the human body.
Thus, in a preferred embodiment, the apparatus of the invention will be a catheter for analyzing infra-red radiation of a blood vessel. Such a preferred device will comprise at least two fibers capable of transmitting the radiation and capable of placement along an axis of the vessel proximate to a plaque-containing locus of an interior wall of the vessel. At least one of the fibers will be a reference fiber coated on its distal end with a material that substantially prevents optical radiation from entering it, and at least one of the other of the fibers will be a signal fiber whose distal end is optically connected to an optically reflective surface capable of directing optical radiation arising radially to its distal end into and along its shaft. Such a preferred device will also have a balloon encasing the distal ends of each of the fibers, which balloon upon inflation will substantially limit the flow of fluids within the blood vessel. In addition, the balloon will substantially exclude fluids between the fibers and the wall of the vessel most proximate to the locus to be tested. The balloon will be transparent to or opaque to the radiation arising inside the vessel and will have an inner surface exhibiting spatially constant optical radiation emissivity. This inner surface of the opaque balloon will be one which emits a black body spectrum. The catheter will be one having a guidewire. It will also have a detector, optically connected to a proximal end of each of the fibers, and capable of detecting a difference in the radiation between the locus and average optical radiation along the wall of the vessel. The detector will further comprise a multi-wavelength radiometer with a spinning circular variable filter, the filter being such that its transmission wavelength is a function of its angle of rotation. The distal ends of the fibers will be offset from one another a distance sufficient to allow sampling of radiation emitted from either fiber to pass the filter at a substantially identical position on the filter. Further, the radiometer will be optically connected to at least one photoelectric device capable of converting the transmitted and filtered radiation into an electrical signal, which signal is capable of being digitized, and which digitized signal is mathematically fitted to a curve selected from a spectrum of curves for black bodies held at temperatures between approximately 300-310xc2x0 K, where the curves are plotted as numbers of photons emitted from each of the black bodies for each of the wavelengths.
The invention also relates to an analytical method, suitable in certain embodiments for diagnosing medical conditions. Thus, the invention relates to a method for analyzing optical radiation of a locus in a vessel wall. The method of the invention comprises placing at least one optical fiber capable of transmitting radiation proximate to the locus. In preferred embodiments, the placement of the fiber and balloon is accomplished by catheterization. Either prior to or after placement proximate to the locus to be analyzed, a balloon encasing a distal end of the fiber is inflated within the vessel to cause the balloon to limit flow of fluids within the vessel. As previously detailed, the balloon is transparent to or opaque to the thermal radiation and has an inner surface exhibiting spatially constant optical radiation emissivity. The methods of the invention further call for transmitting the radiation along the fiber to a detector capable of detecting a difference in the radiation between the locus and the average optical radiation along the vessel wall.
More specifically, the invention relates to a method of detecting plaque at risk of rupturing along a blood vessel. This preferred method comprises inserting a guidewire into the blood vessel to be diagnosed and then catheterizing the vessel along the guidewire with at least two fibers capable of transmitting infra-red radiation along an axis of the vessel proximate to a plaque-containing locus of an interior wall of the vessel. Thereafter, the steps of the method of the invention is carried out as described above.
The invention also relates to a method of surgically treating a patient with a plurality of plaque loci within a vessel. Such a method comprises determining which one or more of the plurality of plaque loci has a temperature elevated above that of the average vessel wall temperature. Once such a determination is made, the surgeon removes or reduces the plaque loci found to have an elevated temperature. This method has as its determination step the methods described above for analyzing optical radiation of plaque locus in a vessel wall. Once plaque at risk is identified, a number of therapies may be used to reduce the risk.
Accordingly, it is an object of the present invention to identify patients who have coronary atherosclerotic plaque at risk of rupture by identifying the specific plaque(s) at risk. Another object of the present invention is to identify patients at risk for arterial restenosis after angioplasty or atherectomy by identifying the specific arterial site(s) at risk. A further object of the present invention is to identify patients at risk of transplant vasculopathy. Another object is to identify patients at risk for stroke, loss of mobility, and other illnesses by identifying sites of potential plaque rupture in the carotid arteries, the intracerebral arteries, the aorta, and the iliac and femoral arteries. Another object of the present invention is to identify patients who have arterial areas of lower rather than higher temperature, such as an area of extensive scarring, a lipid pool with no cellular infiltration, or an area of hemorrhage and thrombosis which has yet to be colonized by inflammatory cells. The delineation of a cholesterol pool is useful in following the regression of plaques. Identifying such areas for follow-up study will localize those likely to be inflamed in the future.
Yet another object of the present invention is to deliver specific local therapy to the injured areas identified by the catheter. These therapies include, but are not limited to, therapies which prevent or limit inflammation (recruitment, attachment, activation, and proliferation of inflammatory cells), smooth muscle cell proliferation, or endothelial cell infection, including antibodies, transforming growth factor-xcex2 (TGF-xcex2), nitric oxide (NO), NO synthase, glucocorticoids, interferon gamma, and heparan and heparin sulfate proteoglycans, and the various complementary DNAs that encode them.
The invention""s methods and devices will have a number of utilities. Each will reduce morbidity and mortality from coronary and carotid artery atherosclerosis. Each will reduce the incidence of restenosis and thus the need for repeated angioplasties or atherectomies. Each will also reduce the incidence of vasculopathy in organ-transplant patients. In turn, these outcomes will produce the benefits of better health care, improved public health, and reduced health care costs. These and other uses of the present invention will become clearer with the detailed description to follow.